Biography: I am a physician scientist focusing on Pediatric Oncology at Dana-Farber Cancer Institute (DFCI) and Harvard Medical School. I received formal scientific and medical training at the University of Tokyo, Japan. I began my postdoctoral research fellowship under the primary mentorship of Dr. A. Thomas Look in the Department of Pediatric Oncology at DFCI in 2017. My career focus is on understanding the spatiotemporal regulation of phosphatase tumor suppressors in pediatric malignancies, and the use of targeted activation of these unique group of enzymes through medicinal chemistry approach as a mechanism of deriving novel therapies for pediatric tumors. Advances in understanding of the biology of protein phosphatase 2A (PP2A) both in physiological and pathological conditions will lead to novel therapeutics with reduced toxicity and ultimately, improvement in patient outcomes in pediatric malignancies.
Lay Description: Several years ago, our team has identified perphenazine (PPZ) as an FDA-approved antipsychotic drug that unexpectedly kills T cell acute lymphoblastic leukemia (T-ALL) cells through its activation of PP2A, a critical phosphatase and a tumor suppressor that removes phosphates from a key regulatory molecule that mediates the proliferation of tumor cells. In my most recent research, I have discovered an analogue of PPZ that is highly effective as an antitumor agent in T-ALL mice models, and significantly extends overall survival of the treated mice. In addition, the identified PP2A activating compound is surprisingly tolerable in these preclinical mice models without affecting the maintenance and proliferation of normal cells such as the bone marrow cells. Stimulated by these findings, in this research supported by the When Everyone Survives Foundation, I will study the molecular mechanisms of how this PP2A activating compound creates its exceptionally wide therapeutic window. Addressing such mechanisms is of paramount importance to advance a clinical candidate drug of this class into Phase I clinical trials in patients with childhood hematologic malignancies.
Researcher - Dr. Davide Seruggia, PhD
Overview - Dr. Seruggia is an Instructor in Pediatrics at Harvard Medical School. He obtained a degree in Medical Biotechnology in Milan, Italy, and a PhD in Molecular Biology at the CNB-CSIC in Madrid, Spain. In 2015 he joined the laboratory of Stuart Orkin at Boston Children’s Hospital, where he trained in hematology, stem cell biology and genomics. In Boston, Dr. Seruggia used genome editing to explore the role of epigenetic factors in the context of mouse embryonic stem cells, and generated a series of mouse model to study how chromatin modifiers control hematopoiesis, erythropoiesis and the expression of globin genes. His current research is focused on the role of chromatin modifiers and cis-regulatory sequences in pediatric malignancies.
B-cell derived acute lymphoblastic leukemia is the most common type of blood malignancy in children. The genetic make-up of B-ALL is diverse and includes chromosomal aberrations (hyperdiploidy; hypodiploidy), translocations (i.e. BCR-ABL1; ETV6-RUNX1; others involving KMT2A) in combination with other mutations at a subset of genes. One of these is ARID5B, a broadly expressed transcription factor whose function is poorly understood. In this proposal, we will use an Arid5b null mouse model that we generated in our laboratory to investigate the function of ARID5B in hematopoiesis and understand its role in developing B-ALL. Next, we will focus on sequence variation at regulatory regions of ARID5B, where mutations accumulate in patients. Using a dense mutagenesis approach, we will dissect mutations at enhancers and elucidate how these mutations are linked to development of leukemia. Taken together, results from this work will shed light on one of the most common mutations in B-ALL and suggest new targets for diagnosis, stratification and therapy.
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